a principled account of how the activity of many functionally specialized brain areas can be integrated to generate a unified perceptual scene that can in turn control behavior in an adaptive manner system (Tononi et al., Lumer et al., Sporns et al., Cerebral Cortex, 1992, 1997, 2000 etc). Most importantly, I have worked for many years on a theoretical framework aimed at characterizing consciousness at the fundamental level, with the explicit aim of developing a testable scientific theory of the necessary and sufficient conditions for conscious experience (Tononi et al. Science 1998, PNAS 1994, 1996, 1999, Trends in Cognitive Sciences 1999 etc.). This work has culminated in the information integration theory of consciousness (Tononi, BMC Neuroscience, 2004 and several other publications including books). According to the theory, consciousness does not arise as a property of brain cells as such, but originates from the unique capability of certain structures within the thalamocortical system to integrate a large amount of information in a short period of time. The theory introduces a measure of such capacity, called ?, and a way to identify complexes, or subsets of elements that can integrate information. As shown in recent publications, the information integration theory can account for several neurobiological observations concerning consciousness, including: i) the association of consciousness with certain neural systems rather than with others; ii) the fact that neural processes underlying consciousness can influence or be influenced by neural processes that remain unconscious;iii) the reduction of consciousness during dreamless sleep and generalized seizures;iv) the time requirements on neural interactions that support consciousness. At present, these measures are being validated using both computer simulations and imaging data obtained from human subjects. Specifically, the information integration theory is being put to test by examining (approximated) differences in ? between conscious and unconscious subjects and between conscious and unconscious brain processes. These studies are being pursued in my own laboratory using a combination of TMS and high-density EEG, and in collaboration with colleagues at the Keck Laboratory. These objective measures of information integration in the brain are beginning to be applied to psychiatric disorders, primarily schizophrenia and dissociative disorders, which are increasingly conceptualized as disorders of the functional connectivity between multiple brain areas and thus as disorders of conscious integration. Taken together, these examples should provide some evidence that I am willing to address important but risky scientific problems, accomplished at integrating different conceptual and experimental approaches, versed at attracting strong collaborators, determined to persevere in the face of considerable difficulties and, most importantly, that I have a record of developing innovative approaches and bring them to a successful conclusion. HOW WILL THE NEW RESEARCH DIRECTION DIFFER FROM THE NOMINEE'S PAST OR CURRENT WORK? In the past, my laboratory has focused on obtaining essential new genetic, molecular, and neurophysiological data that were needed to constrain a comprehensive hypothesis of sleep function. These new data, together with a 4 Tononi critical reading of the vast knowledge accumulated over the past eighty years, have finally led to the formulation of the synaptic homeostasis hypothesis. It is now time to test the hypothesis according to several of its most relevant and surprising predictions. This calls for a very different approach. I will have to engage the help of several colleagues to perform neuroimaging experiments to test rigorously the prediction that wakefulness is associated with a rising metabolic cost while sleep recalibrates the brain's metabolic baseline. I will also have to examine the prediction that the number of cortical synapses increases during wakefulness and decreases during sleep, as can be done for instance by means of dual-photon microscopy. Moreover, I will need to perform stimulation experiments (electrical stimulation/local field potential recordings in animals and TMS/EEG in humans) to verify that mean synaptic efficacy is indeed higher in the evening and decreases after sleep. Finally, I will have to investigate whether sleep is associated with protein markers of synaptic downscaling, and the detailed mechanisms by which downscaling is obtained. These diverse experimental tests are crucial if the validity of the hypothesis is to be established stringently. WHY DOES THE NATURE OF THE RESEARCH FAVOR THE NDPA SELECTION PROCESS OVER THE STANDARD PEER REVIEW PROCESS? So far, a very minor portion of my work has received NIH support (RO1 MH65135 2001-2005 to study the effects of sleep deprivation on arylsulfotransferase activity). In light of previous experience, the proposal to test a comprehensive hypothesis about the function of sleep may not be entirely appropriate for the standard peer review process. One reason is that colleagues usually respond with scarce enthusiasm (to say the least) at the thought of addressing squarely a problem that has resisted the efforts of many scientists for a long time. Study sections are by their nature conservative, and I suspect that a grant proposal aimed at [unreadable]Establishing the function of sleep[unreadable] would be met with considerable skepticism, due to the novel and radical nature of the hypothesis. Another reason is that testing the synaptic homeostasis hypothesis spans several different disciplines, from molecular biology to computer modeling to neuroimaging. While peer reviewers could certainly offer good feedback on specific experiments, a study section may be less well-suited to judging the overall significance of a research program that requires such a multi-faceted approach. By contrast, the NDPA would seem to be in an ideal position to determine whether the time may actually be ripe for a reasoned attempt at unraveling the functions of sleep. SELECTED REFERENCES: Cirelli C, Bushey D, Hill SL, Huber R, Kreber R, Ganetzky B, Tononi G. Reduced sleep in Drosophila Shaker mutants, Nature, in press Tononi G and Cirelli C. Sleep and synaptic homeostasis. Sleep Medicine Rev, in press Hill SL, Tononi G. Modeling Sleep and Wakefulness in the Thalamocortical System. J. Neurophys, in press. Cirelli C, Huber R, Gopalakrishnan A, Southard TA, Tononi G. Locus coeruleus control of slow wave homeostasis. J.Neurosci, in press. Tononi G. (2004) An Information Integration Theory of Consciousness. BMC Neuroscience, 5:42. Massimini M, Huber R, Ferrarelli F, Hill H, Tononi G. (2004) The Sleep Slow Oscillation as a Traveling Wave. J. Neurosci, 24:6862-6870. Huber R, Ghilardi MF, Massimini M, Tononi G. (2004) Local sleep and learning. Nature, 430:78-81. Cirelli C, Gutierrez CM, Tononi G. Divergent effects of sleep and waking on gene expression. Neuron 41: 35-43, 2004. Shaw, P.J., Tononi, G., Greenspan, R.J., and Robinson, S.F. (2002) Stress response genes protect against the lethal effects of sleep deprivation in Drosophila melanogaster. Nature, 417:287-291. Shaw PJ, Cirelli C, Greenspan RJ, Tononi G. Correlates of sleep and waking in Drosophila Melanogaster. Science, 287: 1834-1837, 2000. Tononi, G. and Edelman, G.M., Consciousness and Complexity, Science, 282:1846-1851, 1998. Cirelli, C., Pompeiano, M., and Tononi, G. (1996) Neuronal gene expression in the waking state: a new role of the locus coeruleus. Science, 274: 1211-1215. 5 Tononi, Giulio h Principal Investigator/Program Director Tononi, Giulio BIOGRAPHICAL SKETCH NAME POSITION TITLE Tononi, Giulio Professor EDUCATION/TRAINING INSTITUTION AND LOCATION DEGREE YEAR(s) FIELD OF STUDY Scuola Normale Superiore, Pisa, Italy Scuola Normale Superiore, Pisa, Italy University of Pisa Medical School, Italy M.D. Ph.D. Specialist 1985 1988 1989 Neurobiology Psychiatry A. Positions and Honors 1985-1990, Fellow, Scuola Normale Superiore and Dep. Physiology, University of Pisa, Italy; 1988, Fellow, Dept. Experimental Medicine, University of Lyon, France; 1988, Medical officer, Military Center for Applied Research, Pisa; 1990-1993, Fellow in Theoretical Neurobiology, The Neurosciences Institute, New York; 1993-2000, Senior Fellow in Theoretical and Experimental Neurobiology, The Neurosciences Institute, San Diego; 1999-2000, Associate Professor, The Scripps Research Institute, Department of Neurobiology; 1999-2000, Institute Chair in Theoretical and Experimental Neuroscience, The Neurosciences Institute, San Diego; 2001-Present, Professor, Department of Psychiatry, University of Wisconsin/Madison. Honors and Awards 1992, Award for 'Best young scientist'of the Italian Physiological Society;2001, American Psychiatric Association Frontiers of Science Distinguished Psychiatrist Award;1988, Member, European Sleep Research Society;1992, Member, Society for Neuroscience;1999, Member, Sleep Research Society;1999, Editorial Board of Consciousness and Cognition;2003, Editorial Board of J. Sleep Research. B. Selected peer-reviewed publications (from >100): Cirelli C, Bushey D, Hill SL, Huber R, Kreber R, Ganetzky B, Tononi G. Reduced sleep in Drosophila mutants, Nature, in press Tononi G and Cirelli C. Sleep and synaptic homeostasis. Sleep Medicine Rev, in press. Esser SK, Hill SL, Tononi G. Modeling the effects of TMS on cortical circuits J Neurophys, in press. Hill SL, Tononi G. Modeling Sleep and Wakefulness in the Thalamocortical System. J Neurophys, in press. Cirelli C, Huber R, Gop A, Southard T, Tononi G. (2004) Locus ceruleus control of slow wave homeostasis. J Neurosci, in press. Tononi G. Consciousness, information integration, and the brain. Prog. Brain Res, in press. Tononi G. (2004) An Information Integration Theory of Consciousness. BMC Neuroscience, 5:42. Huber R, Ghilardi MF, Massimini M, Tononi G. (2004) Local sleep and learning. Nature, 430:78. Cirelli C, Tononi G. (2004) Locus ceruleus control of state-dependent gene expression. J Neurosci, 24:5410. Cirelli C, Guterez C, Tononi G (2004). Divergent effects of sleep and waking on gene expression.Neuron 41:35. Massimini M, Huber R, Ferrarelli F, Hill H, Tononi G. (2004) The Sleep Slow Oscillation as a Traveling Wave. J Neurosci, 24:6862. Salbaum JM, Cirelli C, Walcott E, Krushel LA, Edelman GM, Tononi G. (2004) Chlorotoxin-mediated disinhibition of noradrenergic locus coeruleus neurons using a conditional transgenic approach. Brain Res 1016:20. Ferrarelli F, Haraldsson, MH, Barnhart TE, Roberts ADF, Massimini M, Stone CK, Kalin NH, Tononi G. (2004) A [17F]-fluoromethane PET/TMS study of effective connectivity. Brain Res Bull, 64:103. 1